At present, in the development of drugs for preventing or treating Alzheimer's disease (abbreviated as AD) for which a fundamental therapeutic method has not been established, strategies targeted on secretases are main stream. Among them β-secretase and γ-secretase by which direct effect will be expected are especially paid attention. Therefore pharmaceutical companies and venture enterprises have recently extensively engaged in development of said inhibitors.
In 1999, it has been reported that β-secretase is a β-site APP cleaving enzyme BACE1 (also referred to as BACE, Asp2, or memapsin2), an aspartic acid protease, and β-secretase inhibitor based on the substrate transition state concept established by the study on the same class of protease inhibitors such as renin and HIV which belong to a family of an aspartic acid protease as 3-secretase does, have been reported. Any inhibitor is a peptide-based inhibitor by forming a substrate transition state analogue at a β-secretase cleaving site of mimics Swedish APP Swedish variant-type APP readily produces Aβ. Tung et al. for the first time determined the IC50 value of 30 nM in a 14 residue peptide (P10-P4′ statV) in which a hydroxyethylcarbonylisostere (statine) structure was introduced into a substrate cleaving site of β-secretase. They reported that other substrate transition state analogues (AHPPA, ACHPA) could also inhibit β-secretase (for example, see patent literatures 1 and 2.). Ghosh et al. searched various compounds containing hydroxyethyleneisostere, and discovered that OM 99-2 and OM 003 had strong inhibitory activity (Ki=1.6 nM/Ki=0.3 nM respectively) (for example, see patent literature 1.).
The present inventors also designed BACE1 inhibitor KMI-008 as the translation state analogue using hydroxymethycarbonyl (HMC) isoster used in development of renin, HIV-protease inhibitor, or plasmepsin inhibitor which is a special enzyme of malaria protozoa, and using these compounds as a lead compound, KMI-358 and KMI-370 have been developed. Furthermore, BACE1 inhibitors KMI-429 and KMI-684 which are more excellent for chemical stability and more excellent in the inhibition activity have been found (See patent document 2.).
These compounds have strong BACE1 inhibiting activity, but have a peptide structure in their molecules, and therefore, it is supposed that they may be unstable to enzymes in a living body. Furthermore, in considering the action site of β-secretase inhibitor, the drug is necessary to pass through the blood brain barrier and therefore, there are many points to be considered in its development such as a molecular size and hydrophilic and hydrophobic valance.
To conquer these points, a lower molecular BACE1 wherein a part of peptide chin is substituted by an aromatic compound or isophthalic acid by foreign and domestic several research groups was reported (See Non patent 3 and Nonpatent 4.).    [Patent literature 1] WO 2001/000665    [Patent literature 2] WO 2004/076478    [Non patent literature 1] Nature, 402, 537-540 (1999)    [Non patent literature 2] J. Med. Chem., 45, 259-262 (2002)    [Non patent literature 3] J. Med. Chem., 47, 158 (2004)    [Non patent literature 4] J. Med. Chem., 47, 6447 (2004)